Beta-(2, 6-dihalophenyl) ethylamino guanidines and the salts thereof



3,383,409 ,6-(2,6-DIHALO?HENYL)ETHYLAMINO GUANI- DINES AND THE SALTSTHEREOF J olm Bernard Bream, Redbourn, Claude Wolfgang Picard,

Welwyn Garden City, and Trevor George White, Kings Langley, England,assignors to Dr. A. Wander S.A., Bern, Switzerland, a corporation ofSwitzerland No Drawing. Continuation-impart of application Ser. No.453,172, May 4, 1965. This application Nov. 10, 1966, Ser. No. 593,311

3 Claims. (Cl. 26ti501.14)

ABSTRACT OF THE DISCLOSURE 2.6-dihalogenated phenyl ethylaminoguanidinecompounds which exhibit anti-hypertensive pharmacological propertieswithout causing a large increase in the blood pressure or in the pulserate for prolonged periods after administration and which have thefollowing formula:

gnu

l' lnl wherein Hal stands for halogen; and (b) the pharmaceuticallyacceptable acid addition salts of (a).

This application is a continuation-in-part application of our copendingUS. patent application Ser. No. 453,172 filed May 4, 1965 and nowabandoned.

It has been found that some new phenylalkylaminoguanidines havehypotensive activity and are superior in this regard to known compoundshaving this action. They are compounds having the general formula:

as well as acid addition salts thereof. In Formula I, a denotes astraight alkylene group with 2 or 3 carbon atoms. R and R which may bethe same or different, represent hydrogen, halogen, methyl, ethyl,methoxy, or ethoxy.

Specific preferred compounds according to the invention are,B-phenethylaminoguanidine, 'y-phenylpropylaminoguanidine,fi-(o-fiuorophcnyl)ethylaminoguanidine,,3-(2,6-dichlorophenyl)ethylaminoguanidine and acid addition saltsthereof.

The hypotensive action of phenylalkylaminoguanidines of Formula I andtheir acid addition salts is based on their sympatholytic activity.Pharmacologically this can be seen in a diminution of the nictitatingmembrane contraction on preand postganglionic stimulation of thecervical sympathetic nerve of the cat or the guinea-pig. This effect isproduced, at a comparable or lower level of attendant toxicity bysmaller amounts of the compounds according to the invention than ofknown hypotensive agents.

Moreover, some of the compounds according to the invention, especiallythe 2,6-dihalogenated phenylalkylaminoguanidines, are substantially freefrom certain undesirable side-elfects which are usually observed onpreviously known hypotensive agents. These side-effects, consisting in arise in blood pressure of a shorter or longer duration and anacceleration of the pulse just after administration of the drug andbefore the onset of the desired fall in blood pressure, are opposite tothe intended effect, and require certain preventive measures. So,previously known hypotensive agents must be used with great caution andinitially in gradually increasing doses until the desired response isobtained.

States Patent 3,383,409 Patented May 14, 1968 The compounds of Formula Iabove and their acid addition salts may be obtained by hydrogenatingphenylalkylideneaminoguanidines or phenylalkenylideneaminoguanidines ofthe formula:

R (III) in which A, R; and R have the meaning given above, withaminoguanidine or an acid addition salt thereof.

The phenylalkylaminoguanidines of Formula I and their acid additionsalts may also be produced by reacting phenylalkylhydrazines of theformula:

ANIINH2 R (IV) in which A, R and R have the meaning given above, with acompound of the formula:

2 H2Nd=NH in which Z represents a cleavable radical, especially analkoxy or alkylthio group or an l-azolyl group, e.g. a lpyrazolyl or 1-(3,5-dimethyl)pyrazoly1 group, or an acid addition salt thereof. Apreferred method consists in reacting the phenylalkylhydrazines ofFormula IV with S-methylisothiourea or an acid addition salt thereof,such as S-methylisothiouronium sulphate or S-methylisothiouroniumnitrate. If a S-alkylisothiouronium sulphate is used as startingmaterial, the reaction product is preferably not isolated in the form ofthe sulphate, but transformed into the nitrate, for instance by additionof barium nitrate; by proceeding in this way, a purer product can beobtained.

The compounds of the general Formula I and their acid addition salts mayalso be obtained by reacting phenylalkylhydrazines of the Formula IV, oracid addition salts thereof, with cyanamide.

The phenylalkylhydrazines (IV) used as starting materials may beobtained, for example, by reacting the corresponding phenylalkylchlorides with hydrazine.

Insofar as there are obtained free bases by using the proceduresdescribed above, they can be subsequently converted, if desired, intotheir acid addition salts. On the other hand, the bases can be liberatedfrom the acid addition salts obtained by the procedures described above.

The acid addition salts of phenylalkylaminoguanidines of Formula Iinclude those with the usual inorganic and organic acids, eg withcarbonic acid, hydrochloric acid, hydrobromic acid, sulphuric acid,nitric acid, phosphoric acid, acetic acid, maleic acid, oxalic acid,tartaric acid,

toluene-sulphonic acid and similar acids.

Example 1 gm. (0.625 mole) of aminoguanidine dihydrogen carbonate weresuspended in 1200 m1. of water, and the suspension was treated withdilute (1:1) nitric acid, while stirring, until the pH was 3. Themixture was then treated with 300 ml. of ethanol, and the solutionobtained was heated at reflux. The hot solution was stirred and at thesame time 81 gm. (0.625 mole) of phenylacetaldehyde in 1000 ml. ofethanol were added during 1% hours. The reaction mixture was heated foranother 2 hours at reflux while stirring. The reaction mixture was thenconcentrated in vacuo to a volume of about 1000 ml. Whitish crystals ofa rhombic shape separated out on cooling. After recrystallization frometthanol/diisopropyl ether and treatment with charcoal,fl-phenethylideneaminoguanidine hydrogen nitrate of melting pointl56-157 C. was obtained in a yield of 90% of the theoretical.

11 gm. (0.046 mole) of this salt were dissolved in 90% aqueous aceticacid and hydrogenated with 0.25 gm. of Adams catalyst at roomtemperature and normal pressure. When the theoretical amount of hydrogengas had been absorbed, the catalyst was removed by filtration. Thefiltrate was heated on a water bath and then treated with diisopropylether. 9.8 gm. (89% of the theory) of [3- phenethylaminoguanidinehydrogen nitrate, which melted at 145 C. after recrystallization fromethanol/diisopropyl ether, were obtained on cooling.

The semi-dihydrogen oxalate of the same base showed a melting point(from aqueous ethanol) of 213-214 C. (with decomposition); thehydrochloride showed a melting point (from n-propanol/diisopropyl ether)of 114- 121 C.; the semi-dihydrogen carbonate melted (after washing withethanol/diisopropyl ether) at 109-111 C. (with decomposition); and thehydrobromide showed a melting point (from n-propanol/diisopropyl ether)of 1l9-l20 C.

Example 2 A mixture consisting of 17.4 gm. (0.105 mole) of ,3-(0-methoxyphenyl)ethylhydrazine and 13.9 gm. (0.05 mole) ofS-methylisothiouronium sulphate in 25 ml. of water was heated on a steambath until the evolution of methanethiol ceased. The hot solution wastreated with a hot solution of 13.1 gm. (0.05 mole) of barium nitrate in150 ml. of water and the precipitated barium sulphate was separated byfiltration. The filtrate was concentrated in vacuo. On cooling 10.3 gm.(39% of the theoretical yield) of B-(o-methoxyphenyl)ethylaminoguanidine hydrogen nitrate were obtained inthe form of an off-white powder. Upon recrystallization from water theproduct showed a melting point of 129132 C.

Example 3 A solution comprising 20.7 gm. (0.1 mole) ofB-(pchlorophenyl)ethylhydrazine hydrochloride and 17.9 gm. (0.425 mole)of cyanamide in 100 ml. of water was heated on a steam bath during 8hours. The reaction product was precipitated by adding a solution of 9.3gm. (0.11 mole) of sodium bicarbonate in 200 ml. of water. Thebicarbonate obtained was suspended in 100 ml. of n-propanol and treated,while swirling, with a solution of 1.65 gm. (0.03 mole) of sulphuricacid in 25 ml. of n-propanol. After the evolution of carbon dioxide hadceased, the solution was treated with charcoal and filtered. On cooling2.5 gm. of fi-(p-chlorophenyl)ethylarninoguanidine semidihydrogensulphate in the form of white plates were obtained. By concentration ofthe mother liquors, further 7.1 gm. of this product could be isolated,thus giving a total yield of 9.6 gm. (37% of the theoretical). Whenrecrystallized from aqueous ethanol, the product showed a melting pointof l92-l95 C.

A sample of the product was extracted with chloroform from an alkalineaqueous solution. The solvent was evaporated, and the residue was takenin a small amount of water. Upon addition of nitric acid, thecorresponding hydrogen nitrate was obtained, which, afterrecrystallization from ethanol, showed a melting point of 146-l47 C.(with decomposition).

Example 4 A solution of 34.25 gm. (0.25 mole) of aminoguanidine hydrogennitrate in 250 ml. of 93% ethanol and 50 ml.

of water was heated to reflux and treated dropwise with a solution of37.4 gm. (0.275 mole) of cinnamaldehyde in 150 ml. of 93% ethanol over30 minutes. The solution was then refluxed for a further 3 hours. Thesolution was concentrated in a rotary film evaporator, and on coolinggave 51.8 gm. of cinnamaldehyde guanylhydrazone hydrogen nitrate in theform of pale yellow needles of melting point 194-195 C. (withdecomposition) in a yield of 83% of the theoretical.

A suspension of 39 gm. (0.155 mole) of this product in 1000 ml. ofabsolute ethanol was hydrogenated at C. in the presence of 0.5 gm. ofAdams catalyst until the uptake of hydrogen had ceased. The catalyst wasfiltered oil, and the solution was evaporated to dryness in a rotaryfilm evaporator. There are obtained 38.2 gm. of'y-phenylpropylaminoguanidine hydrogen nitrate in the form of a whitepowder of melting point 72-76 C. in a yield of 98% of the theoretical.Recrystallization from ethanol/diisopropyl ether gave clusters of whiteplates of constant melting point til-84 C.

Example 5 A solution of 96 gm. (0.322 mole) of sodium dichromate and 76ml. (1.38 mole) of concentrated sulphuric acid in 400 ml. of water at 25C. was covered with a layer of 900 ml. of toluene and treated with asolution of 123 gm. (0.82 mole) of 'y-o-tolylpropanol in 200 ml. oftoluene with vigorous stirring. The temperature of the mixture rose to56 C. After allowing the mixture to cool to room temperature, thetoluene layer was separated, combined with 3 x 250 ml. of etherextracts, dried and distilled, to give fi-o-tolylpropionaldehyde in theform of a straw-coloured oil of boiling range 117138 C./13 mm. Hg.

A refluxing solution of 32.9 gm. (0.24 mole) of aminoguanidine hydrogennitrate in ml. of Water and 250 ml. of ethanol was treated with aSolution of 37 gm. (0.25 mole) of p-o-tolylpropionaldehyde, added over45 minutes. After refluxing for a further 2 hours, the solvents wereremoved in a rotary film evaporator, and the residual white solid wastriturated with ether to give 54.7 gm. of*y-o-tolylpropylideneaminoguanidine hydrogen nitrate in the form of anamorphous powder of melting point -158 C. in a yield of 86% of thetheoretical. Two recrystallizations of a sample from water/isopropanolgave white needles of constant melting point 169- 171 C. (withdecomposition).

A suspension of 21.1 gm. (0.079 mole) of'y-o-tolylpropylideneaminoguanidine hydrogen nitrate in 500 m1. ofabsolute ethanol was hydrogenated in the presence of 0.5 gm. of Adamscatalyst until the uptake of hydrogen ceased. After filtering oil. thecatalyst, the filtrate was concentrated in a rotary film evaporator andgave 15.3 gm. of -o-to1ylpropylaminoguanidine hydrogen nitrate in theform of a white solid, which was suspended in diisopropyl ether,filtered and dried. This white precipitate had melting point 121-125 C.Another 1.1 gm. of this product was obtained from the filtrate onstanding, thus giving a total yield of 16.4 gm. (77% of thetheoretical). Two recrystallizations of the main crop from isopropanol,with a carbon treatment, gave white plates of constant melting point of126-129 C.

Example 6 By brominating 2,6-dichlorotoluene under the action of light,reacting the resulting 2,6-dichloro-benzyl bromide with potassiumcyanide, saponifying the resulting 2,6-dichlorobenzyl cyanide to2,6-dichlorophenylacetic acid, reducing the latter with lithium-aluminumhydride, treating the resulting ,3-(2,6-dichlorophenyl)ethanol withthionyl chloride and reacting the resulting ,8-(2,6-dichlorophenyl)ethylchloride with hydrazine hydrate, there was obtained[i-(2,6-dichlorophenyl)ethylhydrazine with a boiling point of 144-148C./8 mm. Hg.

A mixture of 11.3 gm. (0.055 mole) of this hydrazine and 5.85 gm. (0.021mole) of S-methylisothiouronium sulphate in 100 ml. of Water was heatedon a steam bath until the evolution of methanethiol ceased. The hotsolution was treated with a hot solution of 5.55 gm. (0.021 mole) ofbarium nitrate in 100 ml. of water and the precipitated barium sulphatewas separated by filtration. On cooling the filtrate, 5 gm. offi-(2,6-dichlorophenyl)ethylaminoguanidine hydrogen nitrate wereobtained in the form of white needles. After recrystallization fromwater the product showed a melting point of 189-190 C.

Example 7 2,6-dichlorophenylacetaldehyde, obtained by oxidizingfl-(2,6-dichlorophenyl)ethanol with sodium dichromate in sulphuric acid,was reacted in ethanolic solution with aminoguanidine hydrogen nitrate,thus obtaining B-(2,6- dichlorophenyl)ethylideneaminoguanidine hydrogennitrate with a melting point of 226-228 C.

A suspension of 31.5 gm. (0.102 mole) of this salt in 1000 ml. ofabsolute ethanol was heated to C. and shaken under a hydrogen atmospherewith 1 gm. of Adams catalyst. During hydrogenation tWo further 0.5- gm.portions of the catalyst were added. After absorption of the theoreticalquantity of hydrogen (2300 ml.) the catalyst was removed by filtration.The filtrate was concentrated in vacuo, whereupon 13 gm. (49% of theory)of a white, granular solid were obtained. Thefi-(2,6-dichlorophenyl)ethylaminoguanidine hydrogen nitrate after beingrecrystallized twice from n-propanol/water, consisted of fine whiteneedles which melted at 190192 C. On the basis of the mixed meltingpoint the product was found to be identical with the compound obtainedaccording to Example 6.

Example 8 2,6-dichlorophenylacetaldehyde, obtained by oxidizing[3-(2,6-dichlorophenyl)ethanol with sodium dichromate in sulphuric acid,was reacted in ethanolic solution with aminoguanidine hydrochloride,thus obtaining 8-(2,6- dichlorophenyl)ethylideneaminoguanidinehydrochloride with a melting point of 170-173 C.

A suspension of 77.8 gm. (0.276 mole) of this salt in 500 ml. ofabsolute ethanol and ml. of 16% ethanolic hydrochloric acid Was heatedto 45 C. and shaken under a hydrogen atmosphere with 1 gm. of Adamscatalyst. After absorption of the theoretical quantity of hydrogen (6200ml.) the catalyst was removed by filtration. The filtrate wasconcentrated in vacuo and the residue obtained was 3 times crystallizedfrom isopropanol, whereby 70.2 gm. of theory) of fl-(2,6-dichlorophenyl)ethylaminoguanidine hydrochloride in the form of white needles ofmelting point 189-191 C. were obtained. The base, liberated from thishydrochloride showed, after crystallization from ethanol, the meltingpoint of 158- 160 C.

The semi-dihydrogen carbonate of this base melted at Cir tartrate at167-169 C. (after crystallization from isopropanel/ether) and thedihydrogen maleate at 153157 C. (after crystallization fromisopropanol/ether).

Example 9 A solution of 24.0 gm. (0.1 mole) offi-(2,6dichlorophenyl)ethylhydrazine hydrochloride and 17.9 gm. (0.425mole) of cyanamide in ml. of water was heated for 8 hours on a steambath. The reaction product was precipitated by adding a solution of 9.3gm. (0.11 mole) of sodium bicarbonate in 200 ml. of water. Thebicarbonate obtained was suspended in 100 m1. of n-propanol and treated,while swirling, with a solution of 1.65 ml. (0.03 mole) of sulphuricacid in 25 ml. of n-propanol. When the evolution of carbon dioxide hadceased, the solution was treated with charcoal and filtered. From thefiltrate 10.1 gm. of crude [3-(2,6-dichlorophenyl)ethylaminoguanidinesemi-dihydrogen sulphate could be isolated which, afterrecrystallization from ethanol/ water, melted at 212-217 C.

By taking up this product from alkaline aqueous solution withchloroform, evaporating it, taking up the residue with a little waterand adding a small quantity of concentrated nitric acid thecorresponding pure hydrogen nitrate of melting point 190-192 C. Wasobtained, which was identical with the product obtained according toExamples 6 and 7.

Example 10 'y-(2,6-dichlorophenyl)propanol, obtained by subjecting2,6-dichlorobenzyl bromide to a Grignard reaction with magnesium andethylene oxide, was oxidized With sodium dichromate in sulphuric acid to'y-(2,6-dichl0rophenyl)propionaldehyde. This latter was converted byreacting with aminoguanidine hydrogen nitrate into 'y-(2,6-dichlorophenyl)propylideneaminoguanidine hydrogen nitrate, which afterrecrystallization from aqueous ethanol formed white prisms which meltedat 224 C.

12.9 gm. (0.04 mole) of this salt were hydrogenated as described inExample 2 in 500 ml. of absolute ethanol in the presence of 0.5 gm. ofAdams catalyst. After removing the catalyst by filtration the reactionmixture was concentrated in vacuo and diluted with diisopropyl ether,whereby 9.8 gm. (76% of theory) of'y-2,6-dichlorophenyl)propylaminoguanidine hydrogen nitrate wereobtained. Recrystallization from Water/isopropanol gave white plateletswith a melting point of 164-165 C.

By the same procedure as in Examples 1 to 10 there are also obtained,for example, the products mentioned in the following Table I. In thetable I-A, R and R correspond to the groups in Formula I, with themeaning stated earlier. In the column on the right are given in bracketsthe solvents or solvent mixtures from which crystallization waseffected; here el, means ethanol, d, diisopropyl ether, i, isopropanol,m, methanol, p, n-pro- 158-161 C. (after washing with water); thedihydrogen 5 P and W, Water- Example A R, R2 Form Melting pointsemi-dihydro' en sulfate 171-174 C. dec 11 2)2' L III-CH3 H {Hydrolggn(lilitl ate i iq 96-93" C non (GI/d) Semii y ro en sup ate... 178-184 0.el 12 D P- H igt dr n nti'ate 113-119 o. gwl.

emii y rogen sulphate... 171-176 C. decom osition l' 13 O-CHI H{lsiydroigin Igtrate 1. i1 150-151 0. (w/i). p (8/1) erni- 1 yr ogen 511p ate 0. el (1 14 (CHZ)2 H {SHydrggfindnitr-ate.. fi 4 C. (v)

emii y rogen sulp ate 70-173 C. (el/w H {Hydrogen nitrate 133-134 0.(w).

H {Eemi-dihydrogen sulphate." 207-215 C. decomposition (el/w).

Hydrogen nitrate 116-118 0. (e1). H Hydrogen nitrate 160-162 0. (w). Hdo H d0 H do 158-162 C. (w) 4-01 Semi-dihydrogen sulphate. 230 C. (m/d).4-61 Hydrogen nitrate Nil-163 C. (p) H d ('/d). H H H H ..(10 107 C(1/(1) 4-C1 do .1 12 1-126 C. (w). 4-Cl ....do -142" C. (w/i).

Production of tablets.-For the manufacture of tablets, the products ofthis invention can be mixed with mannitol and granulated with water,0.5% sodium alginate or 1% gelatine solution. The dried granulate iscompressed into tablets in the presence of about 5% of talcum, 5% ofcorn starch and 0.1% of magnesium stearate. In this way, there areobtained, e.g. tablets of the following compositions:

(a) {3- 2,6-dichlorophenyl ethylaminoguanidine hydrochloride 5 M annitol90 Corn starch 5 Talcum 2 Magnesium stearate 0.1

(b) ,6- 2,6-dichlorophenyl ethylaminoguanidine hydrochloride 20 Mannitoln 75 Corn starch 5 Talcum 2 Magnesium stearate 0.1

These 102 mg. tablets can be orally administered in the treatment of hyertension in general and especially in the case of essential and renalhypertension. The daily 8 We claim: 1. A compound selected from theclass consisting of (a) 2,6-dihalogenophenylalkylaminoguanidines of theformula:

hydro- References Cited UNITED STATES PATENTS 9/1966 Augstein et al.260564 OTHER REFERENCES Robertson et al., Jour. Med. Chem, vol. 6, No.4, pp. 381-4 (1963) R515.

CHARLES B. PARKER, Primary Examiner.

R. V. HINES, Assistant Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3 ,383,409 May 14 1968 John Bernard Bream et a1.

It is certified that error appears in the above identified patent andthat said Letters Patent are hereby corrected as shown below:

Column 1, line 15, "2.6" should read 2,6 -4; same column 1, lines 20 to25, the left-hand portion of the formula should appear as shown below:

Hal

Column 3, lines 7 and 40, and column 5, lines 25 and 47, and column 6,line 43, "in vacuo"; .-each occurrence, should read in vacuo in italics;same column 3; line 9,"etthanol/diisopropyl" should readethanol/diisopropyl Column 6, line 44, 2,6- dichlorophen" should ready-(2,6dichloropheneline 50, "table I-A," should read Table I-A, afterline 56, insert Table I -.I Columns 5 and 6, Table I, first column, line5 thereof, "(5" should read l5 same Table I, under column "A", line 8thereof, "-(CH )C should read .-(CH

same Table I, under same column "A", line 9 thereof, "-(CH should read-(CH same Table I, under column "R line 1 thereof, "1: m-CH should readIII-CH3 same Table I,

under column "Form", line 11 thereof, "E'emi-dihydrogen" should A readSemi-dihydrogen I Column 7 line 24', after "of" insert patientssufferingfrom Signed and sealed this 16th day of December 1969.

(SEAL) Attest:

WILLIAM E. SCHUYLER, JR.

EDWARD M.FLETCHER,JR.

Commissioner of Patents Attesting Officer

2.6-DIHALOGENATED PHENYL ETHYLAMINOGUANIDINE COMPOUNDS WHICH EXHIBITANTI-HYPERTENSIVE PHARMACOLOGICAL PROPERTIES WITHOUT CAUSING A LARGEINCREASE IN THE BLOOD PRESSURE OR IN THE PULSE RATE FOR PROLONGEDPERIODS AFTER ADMINISTRATION AND WHICH HAVE THE FOLLOWING FORMULA: